CD47 expression is critical for CAR T-cell survival in vivo.

BACKGROUND

CD47 is an attractive immunotherapeutic target because it is highly expressed on multiple solid tumors. However, CD47 is also expressed on T cells. Limited studies have evaluated CD47-chimeric antigen receptor (CAR) T cells, and the role of CD47 in CAR T-cell function remains largely unknown.

METHODS

Here, we describe the development of CD47-CAR T cells derived from a high affinity signal regulatory protein α variant CV1, which binds CD47. CV1-CAR T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. The role of CD47 in CAR T-cell function was examined by knocking out CD47 in T cells followed by downstream functional analyses.

RESULTS

While CV1-CAR T cells are specific and exhibit potent activity in vitro they lacked antitumor activity in xenograft models. Mechanistic studies revealed CV1-CAR T cells downregulate CD47 to overcome fratricide, but CD47 loss resulted in their failure to expand and persist in vivo. This effect was not limited to CV1-CAR T cells, since CD47 knockout CAR T cells targeting another solid tumor antigen exhibited the same in vivo fate. Further, CD47 knockout T cells were sensitive to macrophage-mediated phagocytosis.

CONCLUSIONS

These findings highlight that CD47 expression is critical for CAR T-cell survival in vivo and is a 'sine qua non' for successful adoptive T-cell therapy.

Informations de copyright

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: PC, PN, GK, SG, and CD are co-inventors on patent applications in the fields of T-cell or gene therapy for cancer. SG is a consultant of TESSA Therapeutics, a Data and Safety Monitoring Board (DSMB) member of Immatics, and has received honoraria from Tidal, Catamaran Bio, Sanofi, and Novartis within the last 2 years.